An abnormality in regulation of insulin receptors in Pima Indians is being studied in-vitro using isolated circulating mononuclear cells and cultured diploid fibroblasts. Down regulation has been characterized for the fibroblast and this system is being used to identify metabolites in Pima serum which may effect receptor regulation. Investigation of fibroblasts from Pima and Caucasian subjects suggest that the Pima cells have more receptors, reduced insulin affinity and decreased down regulation. Studies to extend these observations are in progress using isolated monocytes. The effect of down regulation on the insulin sensitivity of cellular processes is being measured using normal and down regulated fibroblasts.